Vincamine Synthesis Essay

1. Introduction

Heterocyclic chemistry is one of the most valuable sources of novel compounds with diverse biological activity, mainly because of the unique ability of the resulting compounds to mimic the structure of peptides and to bind reversibly to proteins [1,2,3,4]. To medicinal chemists, the true utility of heterocyclic structures is the ability to synthesize one library based on one core scaffold and to screen it against a variety of different receptors, yielding several active compounds. Almost unlimited combinations of fused heterocyclic structures can be designed, resulting in novel polycyclic frameworks with the most diverse physical, chemical and biological properties. The fusion of several rings lead to geometrically well-defined rigid polycyclic structures and, thus, holds the promise of a high functional specialization resulting from the ability to orient substituents in three dimensional space. Therefore, efficient methodologies resulting in polycyclic structures from biologically active heterocyclic templates are always of interest to both organic and medicinal chemists.

Compounds with heterocyclic rings are inextricably woven into the most basic biochemical processes of life. If one were to choose a step in a biochemical pathway at random there would be a very good chance that one of the reactants or products would be a heterocyclic compound. Even if this was not true, participation of heterocycles in the reaction in question would almost be certain as all biochemical transformations are catalyzed by enzymes, and three of the twenty amino acids found in enzymes contain heterocyclic rings. Of these, the imidazole ring of histidine in particular would be likely to be involved; histidine is present at the active sites of many enzymes and usually functions as a general acid-base or as a metal ion ligand. Furthermore, many enzymes function only in the presence of certain small non–amino acid molecules called coenzymes (or cofactor), which more often than not are heterocyclic compounds. But even if the enzyme in question contained none of these coenzymes or the three amino acids referred to above, an essential role would still be played by heterocycles as all enzymes are synthesized according to the code in DNA, which of course is defined by the sequence of the heterocyclic bases found in DNA.

Chemotherapy concerns the treatment of infectious, parasitic or malignant diseases by chemical agents, usually substances that show selective toxicity towards the pathogen. The diseases of bodily dysfunction and the agents employed are mainly compounds that affect the functioning of enzymes, the transmission of nerve impulses or the action of hormones on receptors. Heterocyclic compounds are used for all these purposes because they have a specific chemical reactivity for example epoxides, aziridines and β-lactams, because they resemble essential metabolites and can provide false synthons in biosynthetic processes, for example antimetabolites used in the treatment of cancer and virus diseases because they fit biological receptors and block their normal working, or because they provide convenient building blocks to which biologically active substituents can be attached. The introduction of heterocyclic groups into drugs may affect their physical properties, for example the dissociation constants of sulfa drugs, or modify their patterns of absorption, metabolism or toxicity.

Many significant discoveries have been made, however, by the rational development of observation of biological activity made by chance in work designed for other ends, or during the clinical use of drugs introduced for other purposes. The theoretical basis of medicinal chemistry has become much more sophisticated, but is naïve to suppose that the discovery of drugs is merely a matter of structure-activity relationships. The success of a medicinal agent depends on the balance between its desirable pharmacological effects and the harm it may otherwise do to a patient, and this cannot yet be predicated with certainty. Serendipity and luck will doubtless continue to play an important part in new discoveries.

2. Indole: Chemical and Biological Importance

Indole (1, Figure 1) is the parent substance of a large number of important compounds that occur in nature. Indole and the simple alkylindoles are colourless crystalline solids with a range of odours from naphthalene-like in the case of indole itself to faecal in the case of skatole (3-methylindole, 2) (Figure 1). Tryptophan [5] (2-amino-3-(3′-indolyl)propionic acid) (3, Figure 1) is one of the naturally occurring essential amino acids. Higher plants degrade tryptophan to heteroauxin (indole-3-acetic acid, 4), a plant hormone (Figure 1).

Figure 1. Indoles.

The compounds 3-(3′-indoyl) propionic acid (5), indole-3-pyruvic acid (6), and the 1-, 2-, and 5-methylindole-3-acetic acids possess similar activity (Figure 2).

Figure 2. Derivatives of indoles.

Figure 2. Derivatives of indoles.

Bacteria degrade tryptophan to tryptamine [6] (2-(3′-indoyl)ethylamine) (7, Figure 2), which is the basis for some of the condensed ring alkaloids. Indole compounds that carry substituents, especially a hydroxy group, on the benzene ring include serotonin [7] (8, Figure 2) which is a vasoconstrictor hormone that plays a part in conducting impulses to the brain. Bufotenine (9, Figure 2) is found in the skins of toads, toxic mushrooms, and West Indian snuff, psilocybin (10, Figure 2) occurs in certain mushrooms. Both are known for their psychotropic effects [8].

Some indole alkaloids exert considerable pharmacological activity but quite different effects may be obtained even from alkaloids of one genus, e.g., the Strychnos alkaloid strychnine acts powerfully causing muscle contraction, while the toxiferines act as muscle relaxants. Of the clinically useful alkaloids, three groups are notable: (a) the Ergot alkaloids—ergometrine with its direct action on the contraction of uterine muscle, ergotamine for migraine relief and the modified alkaloid, bromocriptine, which suppresses lactation and has some application for the treatment of mammary carcinoma; (b) the Rauvolfia alkaloids, and specifically reserpine, which was the forerunner of the tranquillisers; (c) the dimeric anti-leukemic alkaloids of Catharanthus, vinblastine and vincristine. One of the most exciting discoveries within the field of indole alkaloids has been the recognition of the role played by iridoid precursors such as secologanin. These discoveries have enabled the many diverse structures to be rationalized on the basis of an understanding of their biosynthesis. Indoles are probably the most widely distributed heterocyclic compounds in nature having medicinal importance (Figure 3). Tryptophan is an essential amino acid and as such is a constituent of most proteins; it also serves as a biosynthetic precursor for a wide variety of tryptamine-indole, and 2,3-dihydroindole-containing secondary metabolites. In animals, serotonin (5-hydroxytrytamine) is a very important neurotransmitter in the CNS, and also in the cardiovascular and gastrointestinal systems. The structurally similar hormone melationin (11) is thought to control the diurnal rhythm of physiological functions.

Figure 3. Structures of some naturally occurring indoles.

Figure 3. Structures of some naturally occurring indoles.

Study and classification of 5-hydroxytryptamine receptors has resulted in the design and synthesis of highly selective medicines such as sumatriptan [9] (12) for the treatment of migraine, ondansetron [10] (13) for the suppression of the nausea and vomiting caused by cancer chemotherapy and radiotherapy (Figure 4), and alosetron [11] (14) for the treatment of irritable bowel syndrome.

Figure 4. Structure of indoles used in chemotherapy.

Figure 4. Structure of indoles used in chemotherapy.

Tryptophan-derived substances in the plant kingdom include indole-3-ylacetic acid, a plant growth-regulating hormone, and a huge number and structural; variety of secondary metabolites ‒ the indole alkaloids [12] (Figure 5). In the past, the potent physiological properties of many of these led to their use in medicines, but in most instances these have now be supplemented by synthetic substances, although vincristine, a “dimeric” indole alkaloid is still extremely important in the treatment of leukemia. Brassinin [13] (15) isolated from turnips, is a “phytoalexin”-one of a group of compounds produced by plants as a defence mechanism against attack by microorganisms.

Figure 5. Indoles with important activity in plants and animals.

Figure 5. Indoles with important activity in plants and animals.

The physiological activity of lysergic acid diethylamide (LSD) is notorious. The synthetic indol-3-ylacetic acid derivative indomethacin is used for the treatment of rheumatoid arthritis. LSD (16) has been used in psychiatry for its perceived therapeutic value, in the treatment of alcoholism, pain and cluster headache relief, for spiritual purposes, and to enhance creativity [14]. Indomethacin (17) is a non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins [15].

A number of tubulin polymerization inhibitors characterized by the presence of an indole nucleus have been obtained from natural sources or have been prepared by semi-synthesis. Vincristine and vinblastine are among the earliest anti-tumor agents being recognized since 1,965 as tubulin polymerization inhibitors. These drugs remain of clinical interest. Vincristine [16] (18) is anti-tumor agents being recognized tubulin polymerization inhibitors and used in combination in the treatment of acute lymphoblastic leukemia and against both Hodgkin’s and non- Hodgkin lymphoma. Vinblastine is mainly used in the clinical treatment of advanced Hodgkin’s disease against germ cell cancer of the testes [17]. Many efforts have been taken aiming at the identification of novel, more active, and less cytotoxic semi-synthetic Vinca alkaloids. Among the large number of derivatives synthesized by academic or industrial groups, two semi-synthetic derivatives, vindesine and vinorelbine have been employed in anti-cancer therapy [17].

The indole nucleus is the core structure of a great number of tubulin polymerization inhibitors (Figure 6) [18,19]. The indolyl-3-glyoxamide D-24851 (19) and the 2-aroylindoles D-64131 (20a) and D-68144 (20b) were discovered by Baxter Oncology. Compounds 20 are highly active against various tumors, including those resistant to paclitaxel [20]. Several 2-phenylindoles were designed by von Angerer as simple analogues of 12-formyl-5,6-dihydroindolo[2,1-a]isoquinoline. Among them, indole 2-phenylindole 21 completely blocked microtubule assembly at a concentration of 40 µM [21]. On the basis of the structure of the natural product combretastatin A-4 (CSA4), some 2,3-diarylindoles, known as heterocombretastatins 22, were prepared by Medarde [22]. Flynn et al. reported the tubulin polymerization inhibitory activity of 2,3-diarylindoles 23 and 2-aryl-3-arylcarbonylindoles 24 [23]. Sulfur containing compounds, such as sulfonamide E-7010 [24], thiophene [25] and benzothiophene [23] derivatives, proved effective inhibitors of tubulin polymerization. To our knowledge there have been no reports on the inhibition of tubulin polymerization by arylthio/sulfonylindoles.

Figure 6. Indole derivatives as tubulin inhibitors.

Figure 6. Indole derivatives as tubulin inhibitors.

In this race to synthesize new drugs, indoles have attracted a great deal of attention amongst the scientific community due to their therapeutic uses (Figure 7). Researchers from Roche and Vernalis, respectively, described the discovery of 5-hydroxytryptamine 2c (5-HT2c) agonist 25 based on the pyrazino[1,2-a]indole scaffold [26]. Indeed selectivity is one of the most important points in the design of 5-HT2c agonists, as cardiovascular and psychotomimetic effects have been described these compounds. It recently has been shown that β-carbolines 26 represent a novel class of imidazoline-2 (I2) ligands lacking an imidazoline moiety [27]. For example, harmane, norharmane and 1,2,3,4-tetrahydro-β-carboline (THBC) bind at I2 receptors with high affinity [28] (Ki = 49 nM, 87 nM, and 9.4 nM, respectively). A preliminary structure-affinity study has been conducted; the fully aromatic compounds harmane and norharmane displayed <10-fold) selectivity for I2 versus I1 binding sites, but THBC displayed >1,000-fold I2 selectivity. Some compounds of the benzopyrido[4,3-β] indole class 27 are also reported as DNA intercalaters [29].

Pyrazino[1,2-a]indole-1,4-diones , as simple analogues of gliotoxin (28, Figure 7


Total synthesis of Vincamine:
Reference:Herrmann, J. L.; Cregge,R. J.; Richman, J. E.; Semmelhack, C. L.; Schlessinger, R. H. J. Am. Chem. Soc., 1974, 96, 3702–3703. DOI
Keywords: Sulfide → Sulfoxide • Aminal • CarboxEster enolate+Alkyl-X • Alkyl-X+Enolate • CarboxCl → CarboxAmide • N-H → N-Alkyl • Lactam-6 • ConjAdd Enolate • CarboxAmide enolate+EnoateEster • Bischler-Napieralski • Iminium → Amine • Amine-6 • CarboxEster → CarboxAmide • Pummerer •
Reagents:LiNiPr2 • HMPA (solvent) • TsOH • Oxalyl chloride • KH • LiNiPr2 • Acrylate • POCl3 • AlH(OtBu)3-Li+ • Perbenzoic acid, 3-chloro • NaH • Acetyl chloride • NaOMe • NaOMe •

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